5-hydroxytryptamine (5-HT), also known as serotonin or enteramine, is a vasoactive agent and an endogenous neurotransmitter. It acts on receptors found in the central and peripheral nervous system as well as on blood vessels. Other drugs acting at these receptor sites are known as 5-HT agonists or antagonists. The 5-HT receptors have been divided into several sub-classes, some of which themselves contain subtypes. Examples of subtypes of serotonin receptors are 5-HT1, 5-HT1-like, 5-HT1B, 5-HT1D, 5-HT2, 5-HT3, etc.
Agonists that act preferentially at 5-HT1B and 5-HT1D receptors, the triptans, make up a group of therapeutics that may be used for the treatment of migraine headache. A representative member of this group is sumatriptan succinate (distributed under the name Imitrex™ by Glaxo Wellcome, and described in U.S. Pat. No. 4,816,470). Unfortunately, it has been reported that many patients who experience migraine symptom relief within two hours after receiving a 5-HT agonist, experience migraine symptoms again within the next 24 hours. These subsequent headaches are typically termed “rebound,” “relapse,” “recurrent” or “secondary” headaches.
A variety of analgesics have also been administered to migraine patients. For example, K. M. A. Welch (New Eng. J. Med. 329:1476-1483 (1993)) sets forth the following dosages of analgesics as being useful: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and ibuprofen, 200 mg. However, these agents, when taken alone, are rarely effective in providing complete relief symptoms and, after initial remission, migraine symptoms often return.
The problems that occur with migraine headaches may also be present in other types of headache as well. In all cases, an ideal therapy would reduce or eliminate the symptoms associated with the initial attack and minimize the frequency of later recurrences.